A perspective on muscle phenotyping in musculoskeletal research.

Musculoskeletal research should synergistically investigate bone and muscle to inform approaches for maintaining mobility and to avoid bone fractures. The relationship between sarcopenia and osteoporosis, integrated in the term 'osteosarcopenia', is underscored by the close association shown between these two conditions in many studies, whereby one entity emerges as a predictor of the other. In a recent workshop of Working Group (WG) 2 of the EU Cooperation in Science and Technology (COST) Action 'Genomics of MusculoSkeletal traits Translational Network' (GEMSTONE) consortium (CA18139), muscle characterization was highlighted as being important, but currently under-recognized in the musculoskeletal field. Here, we summarize the opinions of the Consortium and research questions around translational and clinical musculoskeletal research, discussing muscle phenotyping in human experimental research and in two animal models: zebrafish and mouse.

Epidemiology of forearm fractures in women and men in Norway 2008-2019.

The purpose of this paper is to describe rates of forearm fractures in adults in Norway 2008-2019. Incidence rate of distal forearm fractures declined over time in both sexes. Forearm fracture constitute a significant health burden and prevention strategies are needed. PURPOSE: To assess age- and sex-specific incidence rates, and time trends for forearm fractures in Norway, and compare these with incidence rates in other Nordic countries. METHODS: Data on all patients aged 20-107 years with forearm fractures treated in Norwegian hospitals from 2008 to 2019 was retrieved from the Norwegian Patient Registry. Fractures were identified based on International Classification of Disease 10th revision code S52. Age- and sex-specific incidence rates and changes in incidence rates were calculated. RESULTS: We identified 181,784 forearm fractures in 45,628,418 person-years. Mean annual forearm fracture incidence rates per 100,000 person-years were 398 (95% CI 390-407) for all, 565 (95% CI 550-580) for women, and 231 (95% CI 228-234) for men above 20 years. Mean annual number of forearm fractures was 15,148 (95% CI 14,575-15,722). From 2008 to 2019, age-adjusted total incidence rates of forearm fractures S52 diagnoses declined by 3.5% (incidence rate ratio (IRR) of 0.997 (95% CI 0.994-0.999)) in men. The corresponding decline in women was not significant (IRR: 0.999 (95% CI 0.997-1.002)). In the same period, the age-adjusted incidence rates of distal forearm fractures declined by 7.0% in men (IRR = 0.930; 95% CI 0.886-0.965) and 4.7% in women (IRR = 0.953; 95% CI 0.919-0.976). The incidence rates of distal forearm fractures were similar to rates in Sweden and Finland. CONCLUSION: Age-adjusted incidence rates of distal forearm fractures in both sexes declined over time.

Validation of forearm fracture diagnoses in administrative patient registers.

The validity of forearm fracture diagnoses recorded in five Norwegian hospitals was investigated using image reports and medical records as gold standard. A relatively high completeness and correctness of the diagnoses was found. Algorithms used to define forearm fractures in administrative data should depend on study purpose. PURPOSE: In Norway, forearm fractures are routinely recorded in the Norwegian Patient Registry (NPR). However, these data have not been validated. Data from patient administrative systems (PAS) at hospitals are sent unabridged to NPR. By using data from PAS, we aimed to examine (1) the validity of the forearm fracture diagnoses and (2) the usefulness of washout periods, follow-up codes, and procedure codes to define incident forearm fracture cases. METHODS: This hospital-based validation study included women and men aged ≥ 19 years referred to five hospitals for treatment of a forearm fracture during selected periods in 2015. Administrative data for the ICD-10 forearm fracture code S52 (with all subgroups) in PAS and the medical records were reviewed. X-ray and computed tomography (CT) reports from examinations of forearms were reviewed independently and linked to the data from PAS. Sensitivity and positive predictive values (PPVs) were calculated using image reports and/or review of medical records as gold standard. RESULTS: Among the 8482 reviewed image reports and medical records, 624 patients were identified with an incident forearm fracture during the study period. The sensitivity of PAS registrations was 90.4% (95% CI: 87.8-92.6). The PPV increased from 73.9% (95% CI: 70.6-77.0) in crude data to 90.5% (95% CI: 88.0-92.7) when using a washout period of 6 months. Using procedure codes and follow-up codes in addition to 6-months washout increased the PPV to 94.0%, but the sensitivity fell to 69.0%. CONCLUSION: A relatively high sensitivity of forearm fracture diagnoses was found in PAS. PPV varied depending on the algorithms used to define cases. Choice of algorithm should therefore depend on study purposes. The results give useful measures of forearm fracture diagnoses from administrative patient registers. Depending on local coding practices and treatment pathways, we infer that the findings are relevant to other fracture diagnoses and registers.

Forearm fractures - are we counting them all? An attempt to identify and include the missing fractures treated in primary care.

OBJECTIVE: Norway has a high incidence of forearm fractures, however, the incidence rates based on secondary care registers can be underestimated, as some fractures are treated exclusively in primary care. We estimated the proportion of forearm fracture diagnoses registered exclusively in primary care and assessed the agreement between diagnosis for forearm fractures in primary and secondary care. DESIGN: Quality assurance study combining nationwide data from 2008 to 2019 on forearm fractures registered in primary care (Norwegian Control and Payment of Health Reimbursement) and secondary care (the Norwegian Patient Registry). SETTING AND PATIENTS: Forearm fracture diagnoses in patients aged ≥20 treated in primary care (n = 83,357) were combined with injury diagnoses for in- and outpatients in secondary care (n = 3,294,336). MAIN OUTCOME MEASURES: Proportion of forearm fractures registered exclusively in primary care, and corresponding injury diagnoses for those registered in both primary and secondary care. RESULTS: Of 189,105 forearm fracture registrations in primary and secondary care, 13,948 (7.4%) were registered exclusively in primary care. The proportion ranged from 4.9% to 13.5% on average between counties, but was higher in some municipalities (>30%). Of 66,747 primary care forearm fractures registered with a diagnosis in secondary care, 62% were incident forearm fractures, 28% follow-up controls, and 10% other fractures or non-fracture injuries. CONCLUSION: An overall small proportion of forearm fractures were registered only in primary care, but it was larger in some areas of Norway. Failing to include fractures exclusively treated in primary care could underestimate the incidence rates in these areas.

Norwegian forearm fracture incidence based on secondary care may be underestimated by not including fractures treated exclusively in primary care.The mean proportion of forearm fractures exclusively handled in primary care is 7% and varies from 5% to 14% between counties.Fractures treated in primary care can be considered for more accurate national incidence rates. Correct fracture diagnosis needs further investigation.

Is There a Causal Relationship between Physical Activity and Bone Microarchitecture? A Study of Adult Female Twin Pairs.

The reasons for the association between physical activity (PA) and bone microarchitecture traits are unclear. We examined whether these associations were consistent with causation and/or with shared familial factors using a cross-sectional study of 47 dizygotic and 93 monozygotic female twin pairs aged 31-77 years. Images of the nondominant distal tibia were obtained using high-resolutionperipheral quantitative computed tomography. The bone microarchitecture was assessed using StrAx1.0 software. Based on a self-completed questionnaire, a PA index was calculated as a weighted sum of weekly hours of light (walking, light gardening), moderate (social tennis, golf, hiking), and vigorous activity (competitive active sports) = light + 2 * moderate + 3 * vigorous. We applied Inference about Causation through Examination of FAmiliaL CONfounding (ICE FALCON) to test whether cross-pair cross-trait associations changed after adjustment for within-individual associations. Within-individual distal tibia cortical cross-sectional area (CSA) and cortical thickness were positively associated with PA (regression coefficients [ß] = 0.20 and 0.22), while the porosity of the inner transitional zone was negatively associated with PA (ß = -0.17), all p < 0.05. Trabecular volumetric bone mineral density (vBMD) and trabecular thickness were positively associated with PA (ß = 0.13 and 0.14), and medullary CSA was negatively associated with PA (ß = -0.22), all p ≤ 0.01. Cross-pair cross-trait associations of cortical thickness, cortical CSA, and medullary CSA with PA attenuated after adjustment for the within-individual association (p = 0.048, p = 0.062, and p = 0.028 for changes). In conclusion, increasing PA was associated with thicker cortices, larger cortical area, lower porosity of the inner transitional zone, thicker trabeculae, and smaller medullary cavities. The attenuation of cross-pair cross-trait associations after accounting for the within-individual associations was consistent with PA having a causal effect on the improved cortical and trabecular microarchitecture of adult females, in addition to shared familial factors. © 2023 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).

Target Values and Daytime Variation of Bone Turnover Markers in Monitoring Osteoporosis Treatment After Fractures.

The serum bone turnover markers (BTM) procollagen type 1 N-terminal propeptide (P1NP) and C-terminal cross-linking telopeptide of type 1 collagen (CTX) are recommended for monitoring adherence and response of antiresorptive drugs (ARD). BTM are elevated about 1 year after fracture and therefore BTM target values are most convenient in ARD treatment follow-up of fracture patients. In this prospective cohort study, we explored the cut-off values of P1NP and CTX showing the best discriminating ability with respect to adherence and treatment effects, reflected in bone mineral density (BMD) changes. Furthermore, we explored the ability of BTM to predict subsequent fractures and BTM variation during daytime in patients using ARD or not. After a fragility fracture, 228 consenting patients (82.2% women) were evaluated for ARD indication and followed for a mean of 4.6 years (SD 0.5 years). BMD was measured at baseline and after 2 years. Serum BTM were measured after 1 or 2 years. The largest area under the curve (AUC) for discrimination of patients taking ARD or not was shown for P1NP <30 µg/L and CTX <0.25 µg/L. AUC for discrimination of patients with >2% gain in BMD (lumbar spine and total hip) was largest at cut-off values for P1NP <30 µg/L and CTX <0.25 µg/L. Higher P1NP was associated with increased fracture risk in patients using ARD (hazard ratio [HR]logP1NP = 15.0; 95% confidence interval [CI] 2.7-83.3), p = 0.002. P1NP and CTX were stable during daytime, except in those patients not taking ARD, where CTX decreased by 21% per hour during daytime. In conclusion, P1NP <30 µg/L and CTX <0.25 µg/L yield the best discrimination between patients taking and not taking ARD and the best prediction of BMD gains after 2 years. Furthermore, higher P1NP is associated with increased fracture risk in patients on ARD. BTM can be measured at any time during the day in patients on ARD. © 2022 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

Cortical bone structure of the proximal femur and incident fractures.

PURPOSE: Fracture risk is most frequently assessed using Dual X-ray absorptiometry to measure areal bone mineral density (aBMD) and using the Fracture Risk Assessment Tool (FRAX). However, these approaches have limitations and additional bone measurements may enhance the predictive ability of these existing tools. Increased cortical porosity has been associated with incident fracture in some studies, but not in others. In this prospective study, we examined whether cortical bone structure of the proximal femur predicts incident fractures independent of aBMD and FRAX score. METHODS: We pooled 211 postmenopausal women with fractures aged 54-94 years at baseline and 232 fracture-free age-matched controls based on a prior nested case-control study from the Tromsø Study in Norway. We assessed baseline femoral neck (FN) aBMD, calculated FRAX 10-year probability of major osteoporotic fracture (MOF), and quantified femoral subtrochanteric cortical parameters: porosity, area, thickness, and volumetric BMD (vBMD) from CT images using the StrAx1.0 software. Associations between bone parameters and any incident fracture, MOF and hip fracture were determined using Cox's proportional hazard models to calculate hazard ratio (HR) with 95% confidence interval. RESULTS: During a median follow-up of 7.2 years, 114 (25.7%) of 443 women suffered one or more incident fracture. Cortical bone structure did not predict any incident fracture or MOF after adjustment for age, BMI, and previous fracture. Each SD higher total cortical porosity, thinner cortices, and lower cortical vBMD predicted hip fracture with increased risk of 46-62% (HRs ranging from 1.46 (1.01-2.11) to 1.62 (1.02-2.57)). After adjustment for FN aBMD or FRAX score no association remained significant. Both lower FN aBMD and higher FRAX score predicted any incident fracture, MOF and hip fractures with HRs ranging from 1.45-2.56. CONCLUSIONS: This study showed that cortical bone measurements using clinical CT did not add substantial insight into fracture risk beyond FN aBMD and FRAX. We infer from these results that fracture risk related to the deteriorated bone structure seems to be largely captured by a measurement of FN aBMD and the FRAX tool.

Bone Phenotyping Approaches in Human, Mice and Zebrafish - Expert Overview of the EU Cost Action GEMSTONE ("GEnomics of MusculoSkeletal traits TranslatiOnal NEtwork").

A synoptic overview of scientific methods applied in bone and associated research fields across species has yet to be published. Experts from the EU Cost Action GEMSTONE ("GEnomics of MusculoSkeletal Traits translational Network") Working Group 2 present an overview of the routine techniques as well as clinical and research approaches employed to characterize bone phenotypes in humans and selected animal models (mice and zebrafish) of health and disease. The goal is consolidation of knowledge and a map for future research. This expert paper provides a comprehensive overview of state-of-the-art technologies to investigate bone properties in humans and animals - including their strengths and weaknesses. New research methodologies are outlined and future strategies are discussed to combine phenotypic with rapidly developing -omics data in order to advance musculoskeletal research and move towards "personalised medicine".

Estimated Glomerular Filtration Rate (eGFR) based on cystatin C was associated with increased risk of hip and proximal humerus fractures in women and decreased risk of hip fracture in men, whereas eGFR based on creatinine was not associated with fracture risk in both sexes: The Tromsø Study.

PURPOSE: Patients with end-stage kidney disease have an increased fracture risk. Whether mild to moderate reductions in kidney function is associated with increased fracture risk is uncertain. Results from previous studies may be confounded by muscle mass because of the use of creatinine-based estimates of the glomerular filtration rate (eGFRcre). We tested the hypothesis that lower eGFR within the normal range of kidney function based on serum cystatin C (eGFRcys) or both cystatin C and creatinine (eGFRcrecys) predict fractures better than eGFR based on creatinine (eGFRcre). METHODS: In the Tromsø Study 1994-95, a cohort of 3016 women and 2836 men aged 50-84 years had eGFRcre, eGFRcys and eGFRcrecys estimated using the Chronic Kidney Disease Epidemiology Collaboration equations. Hazard ratios (HRs) (95% confidence intervals) for fracture were calculated in Cox's proportional hazards models and adjusted for age, height, body mass index, bone mineral density, diastolic blood pressure, smoking, physical activity, previous fracture, diabetes and cardiovascular disease. RESULTS: During a median of 14.6 years follow-up, 232, 135 and 394 women and 118, 35 and 65 men suffered incident hip, proximal humerus and wrist fractures. In women, lower eGFRcre did not predict fracture, but the risk for hip and proximal humerus fracture increased per standard deviation (SD) lower eGFRcys (HRs 1.36 (1.16-1.60) and 1.33 (1.08-1.63)) and per SD lower eGFRcrecys (HRs 1.25 (1.08-1.45) and 1.30 (1.07-1.57)). In men, none of the eGFR estimates were related to increased fracture risk. In contrast, eGFRcys and eGFRcrecys were inversely associated with hip fracture risk (HRs 0.85 (0.73-0.99) and 0.82 (0.68-0.98)). CONCLUSIONS: In women, each SD lower eGFRcys and eGFRcrecys increased the risk of hip and proximal humerus fracture by 25-36%, whereas eGFRcre did not. In men, none of the estimates of eGFR were related to increased fracture risk, and each SD lower eGFRcys and eGFRcrecys decreased the risk of hip fracture by 15-18%. The findings particularly apply to a cohort of generally healthy individuals with a normal kidney function. In future studies, the association of measured GFR using the gold standard method of iohexol clearance with fractures risk should be examined for causal inference. More clinical research is needed before robust clinical inferences can be made.

Are the Relationships of Lean Mass and Fat Mass With Bone Microarchitecture Causal or Due to Familial Confounders? A Novel Study of Adult Female Twin Pairs.

It is not known whether the relationships of lean mass (LM) and fat mass (FM) with bone microarchitecture and geometry are causal and/or are because of confounders, including familial confounders arising from genetic and environment effects shared by relatives. We tested the hypotheses that: (i) LM is associated with cortical bone traits, (ii) FM is associated with trabecular bone traits, and (iii) these relationships of LM and FM with bone microarchitecture and geometry have a causal component. Total body composition was quantified for 98 monozygotic (MZ) and 54 dizygotic (DZ) white female twin pairs aged 31 to 77 years. Microarchitecture at the distal tibia and distal radius was quantified using HRpQCT and StrAx software. We applied the Inference about Causation through Examination of FAmiliaL CONfounding (ICE FALCON) method. Within-individuals, distal tibia total bone area, cortical area, cortical thickness, and trabecular number were positively associated with LM (standardized regression coefficient (ß) = 0.13 to 0.43; all p < 0.05); porosity of the inner transitional zone (ITZ) was negatively associated with LM (ß = -0.22; p < 0.01). Trabecular number was positively associated with FM (ß = 0.40; p < 0.001), and trabecular thickness was negatively associated with FM (ß = -0.27; p < 0.001). For porosity of ITZ and trabecular number, the cross-pair cross-trait association with LM was significant before and after adjustment for the within-individual association with LM (all ps < 0.05). For trabecular number, the cross-pair cross-trait association with FM was significant before and after adjustment for the within-individual association with FM (p < 0.01). There were no significant changes in these cross-pair cross-trait associations after adjustment for the within-individual association (p = 0.06 to 0.99). Similar results were found for distal radius measures. We conclude that there was no evidence that the relationships of LM and FM with bone microarchitecture and geometry are causal; they must in part due to by familial confounders affecting both bone architecture and body composition. © 2020 The Authors. JBMR Plus published by Wiley Periodicals LLC. on behalf of American Society for Bone and Mineral Research.

The effect of maternal and paternal height and weight on antenatal, perinatal and postnatal morphology in sex-stratified analyses.

INTRODUCTION: Low birthweight is associated with diseases later in life. The mechanisms for these associations are not well known. If the hypothesis concerning "maternal constraint" is correct for humans, as shown in animal experiments, we expect the maternal, not paternal, body proportions to influence antenatal growth and those of both parents to influence postnatal growth. We aimed to study the effect of maternal and paternal height and weight on fetal femur length antenatally (gestational weeks 20 and 30) and body length and weight at birth and postnatally (12 and 24 months old) in both sexes. MATERIAL AND METHODS: In this prospective cohort study, 399 healthy pregnant women aged 20-42 years were recruited at The Mercy Hospital for Woman, Melbourne, Australia from 2008 to 2009. Fetal femur length was measured using antenatal ultrasound (gestational weeks 20 and 30). Body length and weight were measured for parents and offspring at birth and postnatally (12 and 24 months). RESULTS: Each standard deviation (SD) rise in maternal weight (15.5 kg) was associated with 0.24 SD (0.5 mm) and 0.18 SD (0.4 mm) longer femur length in female and male fetuses at week 20 and 0.17 SD (0.5 mm) and 0.38 SD (1.1 mm) longer femur length in female and male fetuses at week 30, respectively. In girls, each SD rise in paternal height (7.2 cm) was associated with 0.29 SD (0.6 cm) longer birth length. In boys, each SD rise in maternal height (6.7 cm) was associated with 0.23 SD (0.5 cm) longer birth length. In both sexes, parental height and weight were associated with offspring length and weight at 12 and 24 months (SD ranging from 0.20 to 0.38, length from 0.7 to 1.5 cm and weight from 0.3 to 0.6 kg). The multivariable linear regression analyses were adjusted for parental age, height and weight, maternal smoking, alcohol intake, parity, and ethnicity, all P < 0.05. CONCLUSIONS: Maternal, not paternal, body proportions determined fetal growth in both sexes. Paternal height predicted birth length in girls. In contrast, maternal height predicted birth length in boys. Both parents predicted postnatal body proportions at 12 and 24 months in both sexes.

Prevalence of gestational diabetes and pregnancy outcomes in Nordland and Troms counties 2004­15. / Prevalens av diabetes blant gravide og svangerskapsutfall i Nordland og Troms 2004­15.

BACKGROUND: The aim was to investigate the prevalence of gestational diabetes and pregnancy outcomes in women with gestational diabetes in Nordland and Troms counties. MATERIAL AND METHOD: We included all 1 067 women with type 1 diabetes, type 2 diabetes and gestational diabetes among 34 915 births at four hospitals in Nordland and Troms counties from 2004 to 2015. Prevalence of diabetes was calculated based on ICD-10 codes in patient records for women with diabetes in Nordland and Troms counties, and compared with national prevalence figures from the Medical Birth Registry of Norway. Prevalence of pre-eclampsia, macrosomia (birth weight > 4 500 grams) and caesarian section was calculated for all women with diabetes and all those giving birth in the same region. RESULTS: Prevalence of type 1 diabetes and type 2 diabetes remained stable. Prevalence of gestational diabetes increased from 1.0 % to 4.0 % in Nordland and Troms counties and from 1.0 % to 3.8 % nationally. Prevalence of pre-eclampsia among all women with diabetes fell from 18.8 % in 2004-06 to 12.4 % in 2013-15. In women with diabetes, the prevalence of pre-eclampsia was 4.6 times higher, that of macrosomia was 3.5 times higher, and the proportion of caesarian sections was 2.3 times higher than in the background population. INTERPRETATION: Prevalence of gestational diabetes increased in Nordland and Troms counties, as it did nationally. Prevalence of pre-eclampsia among pregnant women with diabetes fell, but prevalence of pre-eclampsia, macrosomia and caesarean section was higher than in the background population.

Post-fracture Risk Assessment: Target the Centrally Sited Fractures First! A Substudy of NoFRACT.

The location of osteoporotic fragility fractures adds crucial information to post-fracture risk estimation. Triaging patients according to fracture site for secondary fracture prevention can therefore be of interest to prioritize patients considering the high imminent fracture risk. The objectives of this cross-sectional study were therefore to explore potential differences between central (vertebral, hip, proximal humerus, pelvis) and peripheral (forearm, ankle, other) fractures. This substudy of the Norwegian Capture the Fracture Initiative (NoFRACT) included 495 women and 119 men ≥50 years with fragility fractures. They had bone mineral density (BMD) of the femoral neck, total hip, and lumbar spine assessed using dual-energy X-ray absorptiometry (DXA), trabecular bone score (TBS) calculated, concomitantly vertebral fracture assessment (VFA) with semiquantitative grading of vertebral fractures (SQ1-SQ3), and a questionnaire concerning risk factors for fractures was answered. Patients with central fractures exhibited lower BMD of the femoral neck (765 versus 827 mg/cm2 ), total hip (800 versus 876 mg/cm2 ), and lumbar spine (1024 versus 1062 mg/cm2 ); lower mean TBS (1.24 versus 1.28); and a higher proportion of SQ1-SQ3 fractures (52.0% versus 27.7%), SQ2-SQ3 fractures (36.8% versus 13.4%), and SQ3 fractures (21.5% versus 2.2%) than patients with peripheral fractures (all p < 0.05). All analyses were adjusted for sex, age, and body mass index (BMI); and the analyses of TBS and SQ1-SQ3 fracture prevalence was additionally adjusted for BMD). In conclusion, patients with central fragility fractures revealed lower femoral neck BMD, lower TBS, and higher prevalence of vertebral fractures on VFA than the patients with peripheral fractures. This suggests that patients with central fragility fractures exhibit more severe deterioration of bone structure, translating into a higher risk of subsequent fragility fractures and therefore they should get the highest priority in secondary fracture prevention, although attention to peripheral fractures should still not be diminished. © 2019 American Society for Bone and Mineral Research. © 2019 The Authors. Journal of Bone and Mineral Research published by American Society for Bone and Mineral Research.

Adding Marrow Adiposity and Cortical Porosity to Femoral Neck Areal Bone Mineral Density Improves the Discrimination of Women With Nonvertebral Fractures From Controls.

Advancing age is accompanied by a reduction in bone formation and remodeling imbalance, which produces microstructural deterioration. This may be partly caused by a diversion of mesenchymal cells towards adipocytes rather than osteoblast lineage cells. We hypothesized that microstructural deterioration would be associated with an increased marrow adiposity, and each of these traits would be independently associated with nonvertebral fractures and improve discrimination of women with fractures from controls over that achieved by femoral neck (FN) areal bone mineral density (aBMD) alone. The marrow adiposity and bone microstructure were quantified from HR-pQCT images of the distal tibia and distal radius in 77 women aged 40 to 70 years with a recent nonvertebral fracture and 226 controls in Melbourne, Australia. Marrow fat measurement from HR-pQCT images was validated using direct histologic measurement as the gold standard, at the distal radius of 15 sheep, with an agreement (R2 = 0.86, p < 0.0001). Each SD higher distal tibia marrow adiposity was associated with 0.33 SD higher cortical porosity, and 0.60 SD fewer, 0.24 SD thinner, and 0.72 SD more-separated trabeculae (all p < 0.05). Adjusted for age and FN aBMD, odds ratios (ORs) (95% CI) for fracture per SD higher marrow adiposity and cortical porosity were OR, 3.39 (95% CI, 2.14 to 5.38) and OR, 1.79 (95% CI, 1.14 to 2.80), respectively. Discrimination of women with fracture from controls improved when cortical porosity was added to FN aBMD and age (area under the receiver-operating characteristic curve [AUC] 0.778 versus 0.751, p = 0.006) or marrow adiposity was added to FN aBMD and age (AUC 0.825 versus 0.751, p = 0.002). The model including FN aBMD, age, cortical porosity, trabecular thickness, and marrow adiposity had an AUC = 0.888. Results were similar for the distal radius. Whether marrow adiposity and cortical porosity indices improve the identification of women at risk for fractures requires validation in prospective studies. © 2019 American Society for Bone and Mineral Research.

High prevalence of vertebral fractures and low trabecular bone score in patients with fragility fractures: A cross-sectional sub-study of NoFRACT.

PURPOSE: Norway has among the highest incidence rates of fractures in the world. Vertebral fracture assessment (VFA) and trabecular bone score (TBS) provide information about fracture risk, but their importance have not been studied in Norwegian patients with fragility fractures. The objectives of this study were to examine the clinical characteristics of a cohort of women and men with fragility fractures, their prevalence of vertebral fractures using VFA and prevalence of low TBS, and explore the differences between the sexes and patients with and without vertebral fractures. METHODS: This cross-sectional sub-study of the Norwegian Capture the Fracture Initiative (NoFRACT) included 839 patients with fragility fractures. Of these, 804 patients had bone mineral density (BMD) of the total hip, femoral neck and/or spine assessed using dual energy x-ray absorptiometry, 679 underwent concomitant VFA, 771 had TBS calculated and 696 responded to a questionnaire. RESULTS: Mean age was 65.8 (SD 8.8) years and 80.5% were women. VFA revealed vertebral fractures in 34.8% of the patients and 34.0% had low TBS (≤ 1.23), with no differences between the sexes. In all patients with valid measures of both VFA and TBS, 53.8% had either vertebral fractures, low TBS, or both. In the patients with osteopenia at the femoral neck, 53.6% had either vertebral fractures, low TBS, or both. Femoral neck BMD T-score ≤ -2.5 was found in 13.8% of all patients, whereas the corresponding figure was 27.4% using the skeletal site with lowest T-score. Women exhibited lower BMD at all sites and lower TBS than men (1.27 vs. 1.29), (all p < 0.05). Patients with prevalent vertebral fractures were older (69.4 vs. 64.0 years), exhibited lower BMD at all sites and lower TBS (1.25 vs.1.29) than those without vertebral fractures (all p < 0.05). Before assessment, 8.2% were taking anti-osteoporotic drugs (AOD), and after assessment, the prescription rate increased to 56.2%. CONCLUSIONS: More than half of the patients with fragility fractures had vertebral fractures, low TBS or both. The prescription of AOD increased seven fold from before assessment to after assessment, emphasizing the importance of risk assessment after a fragility fracture.

Bone trait ranking in the population is not established during antenatal growth but is robustly established in the first postnatal year.

Efforts to understand the pathophysiology of bone fragility must focus on bone traits during growth. We hypothesized that variance in individual trait ranking in the population distribution is established by genetic factors and is reflected in foetal trait ranking in early pregnancy, but intrauterine factors modify trait ranking in late pregnancy, followed by the reinstating of this ranking during the first postnatal year. Thus, relations with paternal factors are present in early pregnancy but are then lost and subsequently reinstated postnatal. We recruited 399 healthy pregnant women aged 20-42 years from The Mercy Hospital for Woman in Melbourne, Australia. Foetal femur length (FL) and knee-heel length (KHL) were measured by ultrasound during gestation, and FL, KHL, body length and weight were measured in neonates, infants, and parents. The z-scores were calculated using Royston models. Pearson correlation was used to assess tracking and linear mixed models to test the associations. Correlations between FL and KHL z-scores of the same trait at 20 and 30 weeks gestation, at birth, and at 12 and 24 months of age (r = 0.1-0.3) and of body length and weight at birth, and 6, 12 and 24 months (r = 0.3-0.5) became more robust after 6-12 months (r = 0.4-0.8). FL and KHL z-scores at 20 weeks gestation accounted for 4-5% of total variance, while FL, KHL, body length and weight z-scores at birth accounted for 13-26% of total variance in the same traits at 24 months. Maternal FL and KHL were associated with foetal FL and KHL at 20 and 30 weeks, but there were no such associations for paternal FL and KHL with foetal traits during gestation. Both maternal and paternal traits were associated with infant traits. Tracking in traits is not established antenatal but is robustly established at 6-12 months of age.

Women with fracture, unidentified by FRAX, but identified by cortical porosity, have a set of characteristics that contribute to their increased fracture risk beyond high FRAX score and high cortical porosity.

The Fracture Risk Assessment Tool (FRAX) is widely used to identify individuals at increased risk for fracture. However, cortical porosity is associated with risk for fracture independent of FRAX and is reported to improve the net reclassification of fracture cases. We wanted to test the hypothesis that women with fracture who are unidentified by high FRAX score, but identified by high cortical porosity, have a set of characteristics that contribute to their fracture risk beyond high FRAX score and high cortical porosity. We quantified FRAX score with femoral neck areal bone mineral density (FN aBMD), and femoral subtrochanteric architecture, in 211 postmenopausal women aged 54-94 years with non-vertebral fractures, and 232 fracture-free controls in Tromsø, Norway, using StrAx software. Of 211 fracture cases, FRAX score > 20% identified 53 women (sensitivity 25.1% and specificity 93.5%), while cortical porosity cut-off > 80th percentile identified 61 women (sensitivity 28.9% and specificity 87.9%). The 43 (20.4%) additional fracture cases identified by high cortical porosity alone, had lower FRAX score (12.3 vs. 26.2%) than those identified by FRAX alone, they were younger, had higher FN aBMD (806 vs. 738 mg/cm2), and fewer had a prior fracture (23.3 vs. 62.9%), all p < 0.05. They had higher cortical porosity (48.7 vs. 42.1%), thinner cortices (3.75 vs. 4.12 mm), lower cortical and total volumetric BMD (942 vs. 1053 and 586 vs. 699 mg HA/cm3), larger medullary and total cross-sectional areas (245 vs. 190 and 669 vs. 593 mm2), and higher cross-sectional moment of inertia (2619 vs. 2388 cm4) all p < 0.001. When the fracture cases and controls with high cortical porosity were compared, cases had higher cortical porosity, lower cortical vBMD, lower total vBMD, smaller cortical CSA/Total CSA, larger medullary CSA and larger total CSA than controls (all p ≤ 0.05). Thus, fracture cases, unidentified by FRAX, but identified by cortical porosity, had an architecture where the positive impact of larger bone size did not offset the negative effect of thinner cortices with increased porosity. A measurement of cortical porosity may be a marker of other characteristics that capture additional fracture risk components, not captured by FRAX.

Effect of a Fracture Liaison Service on the Rate of Subsequent Fracture Among Patients With a Fragility Fracture in the Norwegian Capture the Fracture Initiative (NoFRACT): A Trial Protocol.

Importance: Fragility fracture is a major health issue because of the accompanying morbidity, mortality, and financial cost. Despite the high cost to society and personal cost to affected individuals, secondary fracture prevention is suboptimal in Norway, mainly because most patients with osteoporotic fractures do not receive treatment with antiosteoporotic drugs after fracture repair. Objectives: To improve secondary fracture prevention by introducing a standardized intervention program and to investigate the effect of the program on the rate of subsequent fractures. Design, Setting, and Participants: Trial protocol of the Norwegian Capture the Fracture Initiative (NoFRACT), an ongoing, stepped wedge cluster randomized clinical trial in 7 hospitals in Norway. The participating hospitals were cluster randomized to an intervention starting date: May 1, 2015; September 1, 2015; and January 1, 2016. Follow-up is through December 31, 2019. The outcome data were merged from national registries of women and men 50 years and older with a recent fragility fracture treated at 1 of the 7 hospitals. Discussion: The NoFRACT trial is intended to enroll 82 000 patients (intervention period, 26 000 patients; control period, 56 000 patients), of whom 23 578 are currently enrolled by January 2018. Interventions include a standardized program for identification, assessment, and treatment of osteoporosis in patients with a fragility fracture that is led by a trained coordinating nurse. The primary outcome is rate of subsequent fracture (per 10 000 person-years) based on national registry data. Outcomes before (2008-2015; control period) and after (2015-2019; intervention period) the intervention will be compared, and each hospital will act as its own control. Use of outcomes from national registry data means that all patients are included in the analysis regardless of whether they are exposed to the intervention (intention to treat). A sensitivity analysis with a transition window will be performed to mitigate possible within-cluster contamination. Results: Results are planned to be disseminated through publications in peer-reviewed journals and presented at local, national, and international conferences. Conclusions: By introducing a standardized intervention program for assessment and treatment of osteoporosis in patients with fragility fractures, we expect to document reduced rates of subsequent fractures and fracture-related mortality. Trial Registration: ClinicalTrials.gov Identifier: NCT02536898.